BMD 420 Chapter Notes - Chapter 1: Insulin Receptor, Cell Membrane, Imatinib

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Published on 20 Feb 2017
School
USA
Department
Biomedical Sciences
Course
BMD 420
Professor
Chapter 1 Pharmacology 9/10/11 2:42:00 PM
I. Chapter 1 Case Study
II. Conformation and chemistry of drugs and receptors
Factors that affect D:R affinity (in increasing strength)
o Van der waals—shifting of electron density causes transient changes in
polarity in response to another nearby molecule
o Hydrogen bonds—H atoms bound to O or N become positively polarized,
allowing them to bind negatively polarized O, N, or S.
o Ionic—atoms w/ excess electrons associate closely w/ electron deficient
atoms.
o Covalent—sharing of electrons; essentially irreversible
§ Drugs that modify receptors in this fashion are called suicide
substrates.
Impact of drug binding on receptor
o Induced fit—altering the conformation of a receptor and thus its function.
o Receptors can exist in multiple conformations:
§ Inactive
§ Active
§ Desensitized/ refractory
Membrane effects of D:R interactions
o Proteins w/ large hydrophobic domains can reside in the plasma membrane.
o Transcription factors and other types of receptors that reside in the cytosol
have only hydrophilic domains.
o Factors that affect drug D:R specificity:
§ Drug & receptor structure
§ Drug solubility in water and plasma membrane
§ Function of the receptor in its cellular environment
III. Molecular and cellular determinants of drug selectivity
Drug selectivity carried out by two mechanisms:
(1) Cell-type specificity of receptor subtypes—receptors that are limited in
their distribution throughout the body allow for more selectivity, such as
imatinib for the BCR-Abl receptor
(2) Cell-type specificity of receptor/effector coupling
IV. Major types of drug receptors
1. Transmembrane ion channels
o Involved in neurotransmission, cardiac conduction, muscle contraction, and
secretion
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o Highly selective for the ions they conduct
o Ligand binding domain can be extracellular, w/in the channel or extracellular
o Three types of ion channels:
§ Ligand-gated
§ Voltage-gated—activated by changes in transmembrane voltage
gradient
§ Second-messenger regulated—activated by binding of ligand to
receptor w/ G-protein coupled cytosolic domain, leading to 2nd
messenger production.
o Two classes of drug that alter the conductance of ion channels
§ Local anesthetics—block conductance of Na through Na channels in
neurons that transmit pain signals from the PNS to the CNS.
§ Benzodiazepines—inhibit neurotransmission in the CNS by increasing
the ability of GABA to bind chloride channels to increase Cl
conductance.
2. Transmembrane G protein-coupled receptors
o Most abundant class of receptors
o Involved in vision, olfaction, and neurotransmission
o Have 7 transmembrane regions w/in a single PP chain, each of which consists
of a single α-helix
o Ligand-binding region contained in the extracellular domain
o G-proteins contain α and βγ subunits noncovalently attached at rest (when
GDP is bound to α).
o Major role is to activate the production of 2nd messengers
§ Gs-- cAMP cascade
§ Gq can activate phospholipase C (PLC), which cleaves PIP2 in the
membrane into IP3 (increases cytosolic Ca concentration) and DAG
(activates PKC)
o β-adrenergic receptors—stimulated by Ep and Nep
§ β-1: play a role in controlling heart rate
§ β-2: relaxation of smooth muscle
§ β-3: mobilization of energy by fat cells
3. Transmembrane receptors w/ enzymatic cytosolic domains
o Involved in cell metabolism, growth and differentiation
o 5 major subtypes:
a) Receptor tyrosine kinases
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Document Summary

9/10/11 2:42:00 pm: chapter 1 case study. Drugs that modify receptors in this fashion are called suicide substrates. Impact of drug binding on receptor: induced fit altering the conformation of a receptor and thus its function, receptors can exist in multiple conformations: Drug solubility in water and plasma membrane. Function of the receptor in its cellular environment. Voltage-gated activated by changes in transmembrane voltage gradient. Second-messenger regulated activated by binding of ligand to receptor w/ g-protein coupled cytosolic domain, leading to 2nd messenger production: two classes of drug that alter the conductance of ion channels. Local anesthetics block conductance of na through na channels in neurons that transmit pain signals from the pns to the cns. Gdp is bound to ): major role is to activate the production of 2nd messengers. Gq can activate phospholipase c (plc), which cleaves pip2 in the membrane into ip3 (increases cytosolic ca concentration) and dag (activates pkc: -adrenergic receptors stimulated by ep and nep.